Recent evidence suggests that disturbances in intracellular signaling may underlie some of the cognitive and neurobehavioral dysfunctions observed in schizophrenia. Studies in humans suggest that the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway is upregulated within the central nervous systems of schizophrenic patients. Our preliminary studies indicate that transgenic mice overexpressing a constitutively active form of the signaling protein Gs- (Gs-*) in forebrain neurons exhibit deficits in two neurobehavioral processes known to be disrupted in schizophrenics, inhibitory gating and explicit learning. Studies in this proposal will examine the effects of increased cAMP/PKA signaling on inhibitory gating and learning in mice to determine whether signaling disturbances could contribute to these endophenotypes of schizophrenia. Studies in Aim 1 will test transgenic mice that overexpress constituents of the cAMP/PKA signaling pathway (i.e. Gs-*, the catalytic subunits of PKA, or a nuclear target of PKA, CREB) in animal models of inhibitory gating and learning to determine whether such mice show deficits in these paradigms (prepulse inhibition, P20/N40 gating, and Morris water maze). Offspring of Gs-* mice crossbred with mice having reduced PKA or CREB activity also will be tested in these behavioral paradigms to determine whether reductions in PKA or CREB can normalize the behavioral deficits produced by the overexpression of Gs-*. Studies in Aim 2 will measure inhibitory gating and learning after localized stimulation of cAMP/PKA activity in forebrain regions of wild-type mice, or after localized inhibition of cAMP/PKA in forebrain regions of Gs-* mice, to determine whether localized pharmacological manipulation of cAMP/PKA activity modifies gating and learning processes. Studies in Aim 3 will determine whether drugs effective at treating symptoms of schizophrenia will normalize gating and learning deficits in mice with upregulated cAMP/PKA activity. These studies will provide important new information about the role that intracellular signaling in cAMP/PKA pathways plays in the expression of gating and learning endophenotypes of schizophrenia.